Human papilloma virus (HPV) is a small double-stranded DNA virus that colonizes various stratified epithelia like skin, oral and genital mucosa, and induces the formation of self-limiting benign tumors known as papillomas (warts) or condylomas. Most of these benign tumors naturally regress due to the influence of host immunological defenses. Some HPVs, however, have oncogenic potential and have been associated with certain types of cancers, See, Lorincz et al., Obstetrics & Gynecology, 79:328-337 (1992); Beaudenon et al., Nature, 321:246-249 (1986); and Holloway et al., Gynecol, One., 41:123-128 (1991).
Infection with HPV is common. HPV can be transmitted sexually, and it is estimated that 20-80% of sexually active adults have been infected. While a majority of infections are asymptomatic, infection can lead to the development of genital warts (which have a prevalence of about 1-5% among adults) and cancer of the anogenital tract. Another type of cancer, cervical cancer, is strongly associated with HPV (Frazer, Genitourin, Med. 72:398-403, 1996), HPV types 6, 11, 16, 18, 31, and 33 are often associated with an increased risk of cancer, with types 16 and/or 18 being detected in more than 90% of cervical carcinomas (van Driel et al., Ann. Med. 28:471-477, 1996). Types 6 and 11 are also associated with anogenital warts. For reviews of papilloma viruses and their associated pathologies, see Shah et al., “Chapter 66: Papillomaviruses,” In: Virology, 3rd Edition, Fields et al., Eds., Raven Press, Philadelphia, pp 2077-2109, 1996, and zur Hansen, J. Natl, Cancer Inst. 92:690-698, 2000.
Verrucae or human warts are benign epidermal tumors caused by human papilloma virus HPV. HPV is a member of the papovavirus family. HPV is a non-enveloped double-stranded deoxyribonucleic acid (DNA) virus that replicates in epithelial cells. This means that HPV has a predilection for the mucosa and skin. Currently, there are more than 70 distinct HPV types recognized each with at least a 10% genome difference. Because papillomaviruses tend to be host-specific and HPV has not been successfully grown in culture; the majority of the research with papilloma virus has been conducted with animal papillomaviruses. Papillomaviruses are considered responsible for several forms of viral infection ranging from relatively benign warts of the skin or mucous membranes to cancer, the most significant being cervical cancer. Papillomaviruses are known to infect mammals, including humans, rabbits, canines, felines, bovines and equines. Papillomaviruses are highly species and tissue-specific, and are characterized by a specific mode of interaction with the squamous epithelia they infect. These viridae colonize various stratified epithelia like skin and oral and genital mucosae, and induce the formation of self-limited benign tumors, known as warts or condylomas.
An immune response against HPV infection is associated with cell mediated immune function rather than humoral immune function. This function is recognized medically as the basis for this anti-viral activity based on increases in CD4 helper and CD8 killer T cells with respect to combating HPV infection. Biologically, this results from Th-1 cell mediated immune responses with release of cytokines to impart human papilloma virucidal activity. Warts as human papilloma infections can occur in various forms, i.e., common warts (verruca vulgaris), plantar warts (verruca plantaris) & genital warts including venereal and inguinal warts. These are prevalent among all racial groups.
Current therapies as warts treatments are divided into three groups: cellular destruct chemical agents, cryotherapy and immunomodulators. Cellular destructive therapies include chemical agents such as podophyllin, trichloroacetic acid, 5-fluorouracil, bleomycin, retinoids, glutaraldehyde, formaldehyde, salicylic acid and cantharidin. With cryotherapy, a wart is exposed to liquid nitrogen for several treatments spread over three to four weeks required to destruct the warts cellular structure. These treatments results in varying success depending on the nature and severity of the wart lesions. The present invention provides a need in the art for more effective treatments of warts.
Melanoma is a serious form of skin cancer in humans. It arises from the pigment cells (melanocytes), usually in the skin. Melanoma is currently increasing at the fastest rate of all cancers in the United States. Without even including melanoma in-situ, it is the seventh most common serious cancer in the United States.
Melanoma has emerged as the primary model for developing immunotherapies for several reasons. Histopathologic evidence of tumor regression is frequently observed within primary melanoma specimens, along with the presence of tumor infiltrating lymphocytes, thus suggesting a prominent role for the immune system in melanoma (Leong et al., 1996 Surg Clin North Am 76: 1355-81). Melanoma cells readily adapt to tissue culture, resulting in the creation of panels of melanoma cell lines to study. The paucity of effective therapies (chemotherapy, radiation) has resulted in a lower threshold for testing immunological therapies in patients with melanoma (Wolchok et al., 2001 Lancet Oncol II: 205-11; Houghton et al., 2001 Curr Opin Immunol 13: 134-40).
Melanomas are aggressive, frequently metastatic tumors derived from either melanocytes or melanocyte related nevus cells. Melanomas make up approximately three percent of all skin cancers and the worldwide increase in melanoma is unsurpassed by any other neoplasm with the exception of lung cancer in women. Even when melanoma is apparently localized to the skin, up to 30% of the patients will develop systemic metastasis and the majority will die (Kirkwood and Agarwala (1993) Principles and Practice of Oncology 7:1-16).
T cells play an important role in tumor regression in most murine tumor models. Tumor infiltrating lymphocytes (TIL) that recognize unique cancer antigens can be isolated from many murine tumors. The adoptive transfer of these TIL plus interleukin-2 can mediate the regression of established lung and liver metastases (Rosenberg, S. A., et al., (1986) Science 233:1318-1321). In addition, the secretion of IFN-γ by injected TIL significantly correlates with in vivo regression of murine tumors suggesting activation of T-cells by the tumor antigens (Barth, R. J., et al., (1991) J. Exp. Med. 173:647-658). The known ability of tumor TIL to mediate the regression of metastatic cancer in 35 to 40% of melanoma patients when adoptively transferred into patients with metastatic melanoma attests to the clinical importance of the antigens recognized (Rosenberg, S. A., et al., (1988) N Engl J Med 319:1676-1680; Rosenberg S. A. (1992) J. Clin. Oncol. 10:180-199).
Melanomas can metastasize either by the lymphatic or haematogenous route. About two-thirds of metastases are originally confined to the drainage area of regional lymph nodes. A regional metastasis can appear as a micrometastasis in the regional lymph nodes identified via sentinel lymph node biopsy. In contrast to macrometastasis, micrometastasis is not clinically recognizable by palpation or by imaging techniques.
Classic modalities of treating melanoma include surgery, radiation and chemotherapy. For example, standard treatment of a primary tumor is to surgically remove the tumor with adequate margins. However the management of in-transit disease remains extremely challenging. Although surgery may be reasonable when the number of lesions is small, this occurs in only the minority of cases. In the past decade immunotherapy and gene therapy have emerged as new and promising methods for treating melanooma.
Currently, a major treatment for cancerous tumors is surgical removal of the affected areas of the tissue, organ, or gland. However, high recurrence rates are a major obstacle to the complete eradication of cancerous cells. It is believed that although the cancer cells in the malignant tumors can be removed surgically, cancerous cells that have invaded the surrounding tissue or lymph nodes frequently cause tumor recurrence. One reason for frequent tumor recurrence may be that during the development of the primary cancer, complete removal of all the cancer cells by surgical procedures is extremely difficult. Although irradiation, chemotherapy and appropriate hormone therapy all induce apoptosis to some extent in tumor cells, higher doses of the drugs or radiation may be required for suppressing the growth of cancer cells, which, in turn, can cause severe side effects on patients.
Novel strategies are clearly needed to improve the clinical outcome of HPV infection and melanoma. The present invention provides a need in the art for more effective treatments of these diseases.